Advanced glycation end products and the progressive course of renal disease

Heidland, A.; Šebeková, Katarı́na; Schinzel, Reinhard

doi:10.1053/ajkd.2001.27414

Cited by 147 publications

(103 citation statements)

References 36 publications

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“…Formation of 3-DG-imidazolone is highly specific for the 3-DG precursor and thus a marker for the accumulation of carbonyl compounds [4,5]. The detrimental effects of AGEs in diabetic and non-diabetic nephropathy have been intensively investigated recently [6]. In vivo, CML is the most widely distributed AGE under oxidative conditions and can exert cellular effects by binding to the AGE receptor RAGE [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Renal accumulation and clearance of advanced glycation end-products in type 2 diabetic nephropathy: effect of angiotensin-converting enzyme and vasopeptidase inhibition

Wihler¹,

Schäfer²,

Schmid³

et al. 2005

Diabetologia

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Aims/hypothesis: Renal accumulation of AGEs may contribute to the progression of diabetic nephropathy. We evaluated the effect of ramipril (a pure ACE inhibitor) and AVE7688 (a dual inhibitor of ACE and neutral endopeptidase) on renal accumulation of the advanced glycation end-product (AGE) 3-deoxyglucosone-imidazolone, carboxymethyllysine (CML) and pentosidine, and on clearance of CML in type 2 diabetes. Methods: Male Zucker diabetic fatty rats (ZDF, Gmi-fa/fa) rats were treated from age 10 to 37 weeks with ramipril (1 mg·kg −1 ·day −1 ), AVE7688 (45 mg·kg −1 ·day −1 ) or without drug. Ramipril and AVE7688 reduced albuminuria by 30 and 90%, respectively. Results: ZDF rats showed increased renal accumulation of the AGE subtypes 3-deoxyglucosone-imidazolone, pentosidine and CML by about 40, 55 and 55%, respectively compared with heterozygous, non-diabetic control animals at the age of 37 weeks. AVE7688 but not ramipril attenuated the renal accumulation of 3-deoxyglucosone-imidazolone, pentosidine and CML and improved CML clearance in ZDF rats. During glycation reactions in vitro, AVE7688 also demonstrated potent chelating activity and inhibited metal-catalysed formation of pentosidine and CML. Conclusions/interpretation: Improved AGE clearance and direct inhibition of AGE formation by chelation may contribute to reduced accumulation of renal AGEs and to the nephroprotective effects of vasopeptidase inhibition in type 2 diabetes.

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Section: Introductionmentioning

confidence: 99%

Renal accumulation and clearance of advanced glycation end-products in type 2 diabetic nephropathy: effect of angiotensin-converting enzyme and vasopeptidase inhibition

Wihler¹,

Schäfer²,

Schmid³

et al. 2005

Diabetologia

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“…The toxic effects of these AGE result from structural and functional alterations in plasma and extracellular matrix (ECM) proteins, in particular, from cross-linking of proteins and interaction of AGEs with their receptors and/or binding proteins. This leads to enhanced formation of reactive oxygen species with subsequent activation of NF κ B and release of pro-inflammatory cytokines, growth factors, and adhesion molecules [16,23,24]. AGE accumulation in collagen, a long-lived structural protein in the extracellular matrix region of the kidney, is thought to effect changes in elasticity, ionic charge, thickness and turnover of basement membrane components [25].…”

mentioning

confidence: 99%

LR-90 a new advanced glycation endproduct inhibitor prevents progression of diabetic nephropathy in streptozotocin-diabetic rats

et al. 2003

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Aims/hypothesis. Advanced glycation and lipoxidation endproducts have been implicated in the pathogenesis of diabetic complications, including diabetic nephropathy. LR-90, a new advanced glycation endproduct inhibitor, was investigated for its effects on the development of renal disease in diabetic rats. Methods. Diabetic animals were randomly allocated into groups receiving LR-90 or vehicle (untreated). Age-and weight-matched non-diabetic rats were studied concurrently. Body weight, plasma glucose, glycated haemoglobin, urinary albumin and creatine excretions were measured serially. Kidney histopathology, AGE accumulation in cells and tissues, protein oxidation, were also examined. In vitro assays were used to assess the possible mechanism of action of LR-90. Results. LR-90 inhibited the increase in albumin and creatinine concentrations, and concentrations of circulating AGE in diabetic rats without any effect on glycaemic control. LR-90 treated-rats also showed higher body weights than untreated diabetic rats. LR-90 prevented glomerulosclerosis, tubular degeneration and collagen deposition in the kidney. AGE-induced crosslinking and fluorescence of tail collagen were reduced by LR-90 treatment. LR-90 also decreased AGE accumulation in kidney glomeruli and nitrotyrosine deposition in the renal cortex. In vitro, LR-90 was capable of reacting with reactive carbonyl compounds and was a more potent metal chelator than pyridoxamine and aminoguanidine. Conclusion/interpretation. LR-90 reduces in vivo AGE accumulation, AGE-protein cross-linking and protein oxidation, and could be beneficial in preventing the progression of diabetic nephropathy. The AGE inhibitory and therapeutic effects of LR-90 could be attributed, at least in part, to its ability to react with reactive carbonyl species and/or potent metal chelating activity that inhibits glycoxidative-AGE formation.

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“…They may therefore be involved in the non-specific progression of chronic nephropathies, and in the progressive sclerosis of the kidney that occurs with age (37). Specific antagonists of RAGE would thus be beneficial in these various conditions, unless other receptors are also able to mediate similar effects when activated by AGEs (38).…”

Section: Discussionmentioning

confidence: 99%

Advanced glycation end products regulate extracellular matrix protein and protease expression by human glomerular mesangial cells

Berrou

Tostivint

Verrecchia³

et al. 2009

Int J Mol Med

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Abstract. Advanced glycation end products (AGEs) may play a role in the pathogenesis of diabetic nephropathy, by modulating extracellular matrix turnover. AGEs are known to activate specific membrane receptors, including the receptor for AGE (RAGE). In the present study, we analyzed the various receptors for AGEs expressed by human mesangial cells and we studied the effects of glycated albumin and of carboxymethyl lysine on matrix protein and remodelling enzyme synthesis. Membrane RAGE expression was confirmed by FACS analysis. Microarray methods, RT-PCR, and Northern blot analysis were used to detect and confirm specific gene induction. Zymographic analysis and ELISA were used to measure the induction of tPA and PAI-1. We show herein that cultured human mesangial cells express AGE receptor type 1, type 2 and type 3 and RAGE. AGEs (200 μg/ml) induced at least a 2-fold increase in mRNA for 10 genes involved in ECM remodelling, including tPA, PAI-1 and TIMP-3. The increase in tPA synthesis was confirmed by fibrin zymography. The stimulation of PAI-1 synthesis was confirmed by ELISA. AGEs increased PAI-1 mRNA through a signalling pathway involving reactive oxygen species, the MAP kinases ERK-1/ERK-2 and the nuclear transcription factor NF-κB, but not AP-1. Carboxymethyl lysine (CML, 5 μM), which is a RAGE ligand, also stimulated PAI-1 synthesis by mesangial cells. In addition, a blocking anti-RAGE antibody partially inhibited the AGE-stimulated gene expression and decreased the PAI-1 accumulation induced by AGEs and by CML. Inhibition of AGE receptors or neutralization of the protease inhibitors TIMP-3 and PAI-1 could represent an important new therapeutic strategy for diabetic nephropathy.

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Advanced glycation end products and the progressive course of renal disease

Cited by 147 publications

References 36 publications

Renal accumulation and clearance of advanced glycation end-products in type 2 diabetic nephropathy: effect of angiotensin-converting enzyme and vasopeptidase inhibition

Renal accumulation and clearance of advanced glycation end-products in type 2 diabetic nephropathy: effect of angiotensin-converting enzyme and vasopeptidase inhibition

LR-90 a new advanced glycation endproduct inhibitor prevents progression of diabetic nephropathy in streptozotocin-diabetic rats

Advanced glycation end products regulate extracellular matrix protein and protease expression by human glomerular mesangial cells

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